Targeting the anti-apoptotic Bcl-2 family proteins is a promising therapeutic strategy for cancer and has been validated by the FDA approval of the Bcl-2 selective inhibitor, venetoclax, for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Given the well-documented importance of Bcl-xL to many types of cancers, including most T-cell acute lymphoblastic leukemia (T-ALL), and its contribution to drug resistance, Bcl-xL has become one of the best validated cancer targets. Unfortunately, the on-target and dose- limiting platelet toxicity associated with the inhibition of Bcl-xL has prevented the use of Bcl-xL inhibitors in the clinic. To circumvent this toxicity, we have applied the Proteolysis Targeting Chimera (PROTAC) technology to design small-molecules that target Bcl-xL to E3 ligases for degradation. Our hypothesis is that Bcl-xL degrading PROTACs (named as Bcl-Ps) designed to recruit an E3 ligase that is minimally expressed in platelets for the targeted degradation of Bcl-xL will have reduced platelet toxicity and improved antitumor activity compared with their corresponding Bcl-xL inhibitors. This hypothesis is supported by our strong preliminary results, including in vivo efficacy data in T-ALL patient-derived xenograft (PDX) mouse models and other tumor xenograft mouse models. In addition, our Bcl-Ps are also potent senolytic agents that can selectively kill senescent cells (SnCs), because SnCs also rely on Bcl-xL for survival. Clearance of chemotherapy-induced SnCs is considered as a novel strategy to prevent or reduce many short- and long-term adverse effects of the chemotherapeutic drugs, as well as cancer relapse and metastasis. Collectively, these findings suggest that Bcl-Ps are superior to conventional Bcl-xL inhibitors as anticancer agents. The goal of this application is to: (1) optimize Bcl-Ps for improved potency, selectivity, drug-like properties, and in vivo efficacy; (2) evaluate the new Bcl-Ps through a series of in vitro and in vivo assays; and (3) evaluate the preclinical efficacy of lead Bcl-Ps in T-ALL PDX models. Upon completion of this project, we aim to produce Bcl-Ps amenable to further evaluation in clinical trials for T- ALL, an aggressive leukemia that currently has no targeted therapies.